Table 2.

Cell death proteins are implicated in homeostatic tissue response to obesity.

Cell death program	Target Protein	Model	Major Findings	reference
Apoptosis/Necroptosis	FADD	HFD or Lepob/obmice	FaddA-KO:	[68]
			↑Energy expenditure and fatty acid oxidation, food intake, mitochondrial content in WAT, insulin sensitivity and glucose tolerance.
			↓FFA, inflammation, hepatic steatosis, WAT mass, weight gain, ATMs
	Caspase-8	Casp8A-OE	↑Apoptosis of adipocytes [66, 67].	[66, 67]
			↑M2 macrophages in WAT, TNF and MCP-1 in WAT [67].
			= Body weight [67].
			↓WAT mass and adiponectin [67].
			Lepob/ob:
			↑Apoptosis in adipocytes, energy expenditure, plasma levels of glucose and triglycerides, glucose intolerance, food intake, WAT macrophages infiltration and hepatic steatosis.
			↓Body weight, leptin and insulin levels [66].
	cFLIP	NASH (HFD) or Lepob/ob mice	↓cFLIP only in liver	[71]
			cFLIPhep-KO(HFD mice):
			↑body and liver weight, hepatic steatosis, inflammation, glucose and fatty acid uptake, plus fatty acid synthesis.
			= Food intake.
			↓Fatty acid β-oxidation, glucose and insulin tolerance
			cFLIPhep-OE (HFD Monkeys):
			↑Liver function and fatty acid metabolism.
			= Body weight.
			↓Hepatic lipid accumulation, fibrosis and inflammatory response
	BID	HFD or HSD	↑Caspase-3 cleavage.	[65]
			Bid−/−:
			↑Insulin sensitivity.
			= Gain weight.
			↓Caspase activation, adipocyte apoptosis, ATMs and hepatic steatosis [48].
	Cyclophilin D	CyclophilinD−/− in HFD	↑Perilipin.	[102]
			Ø Adipocyte cell death.
			= Glucose tolerance, inflammation, ATMs, insulin resistance, weight gain.
			Mitochondria permeability does not play a role in HFD-induce inflammation
	TAK 1	Tak1A-KO in HFD or Lepob/ob mice	↑Apoptotic adipocytes, M2-like ATMs in WAT, energy expenditure, glucose tolerance, food consumption.	[103]
			↓Adipocyte numbers, gain weight and WAT weight
	RIPK1	HFD or Lepob/ob	↑Ripk1 expression in obese mice [78, 79] and human [78].	[78, 79]
			Ripk1 siRNA in HDF:
			↑IL-10, iNKT cells infiltration and insulin sensitivity.
			↓Hepatic inflammation, fat mass, total body weight and ATM [78].
			RIPK1 inhibition (Nec-1) in Lepob/ob:
			↑Increased glucose tolerance
			↓Fasting blood glucose insulin resistance, fat deposition, hepatic triglycerides
			= Body weight, food intake and inflammation [79].
	RIPK3	HFD	↑RIPK3 in WAT and liver of obese humans and mice [72, 104–106]	[72, 104–106]
			Ripk3−/−:
			↑Caspase-8-dependent adipocyte apoptosis and WAT, inflammation, glucose intolerance [72, 104]
			↑Liver injury, lipid accumulation in liver and insulin resistance [104].
			↓insulin signalling in WAT [72].
			Ripk3−/− CDAA diet:
			↑Apoptosis in liver and WAT, body weight, hepatic lipogenesis, fat accumulation, insulin/glucose, levels, MRC complex activity.
			↓Inflammation and fibrosis in liver [106].
			Ripk3−/−Caspase-8hep-KO:
			= glucose tolerance and insulin resistance [72].
			Ripk3−/−Caspase-8−/−:
			↑glucose tolerance and insulin sensitivity [72].
	MLKL	WD or HFD, Lepob/ob LepRdb/db	↑MLKL levels in the liver of obese models [79].	[79, 107]
			Palmitic acid ↑MLKL expression, phosphorylation, oligomerization independently of RIPK3 [107].
			MLKL regulates insulin signalling and sensitivity [79].
			Mlkl−/−:
			↓Body weight, insulin resistance, glucose intolerance [79, 107].
			= Liver inflammation and levels of cell death [79].
			↓Inflammation and liver injury [107].
Pyroptosis	NLRP1	ND/HFD mice or Obese human	= NLRP1 levels in WAT of obese and lean human [93]	[93, 95]
			Nlrp1−/− :
			Spontaneous phenotype ↓IL-18. ↑adipose tissue, glucose intolerance, insulin resistance and
			leptin levels.
			HFD aggravates obesity, metabolic Syndrome, and steatosis in Nlrp1−/− Mice [95]
	NLRP3	HFD mice or Obese human	↑NLRP3 in liver of obese patients [84] and in mice and human WAT [84, 85, 108]	[84–87, 89, 90, 108, 109]
			↑WAT hypoxia and inflammation-related factors regulates NLRP3 expression [84].
			Nlrp3−/− or Nlrp3 silencing.:
			↑Adipogenesis, insulin sensitivity.
			↓Inflammation, IL-1β, IL18, blood glucose, insulin levels, fibrosis [84, 89, 110]
		LPS treatment (no diet)	↑NLRP3, IL-1β	[91]
			↓Mitochondrial function, browning in WAT
	Caspase-1	HFD, Lepob/ob or LepRdb/db	↑Caspase-1 in WAT and liver of obese humans and mice [85, 86, 89, 108]	[85, 86, 89, 90, 108]
			Casp1−/−:
			↑Body weight, adiposity, insulin sensitive, inflammation, CCL2, Leptin and lipid oxidation.
			= Lipid profiles, glucose intolerance, energy expenditure and liver weight.
			↓Adiponectin and IL18 [85, 86].
			Ex-vivo caspase-1 inhibition in human WAT:
			↓IL1-β and IL-18 release [108].
			Caspase-1 inhibition in Ldlr-/- (Leiden Mice):
			↑Insulin sensitivity.
			= Body weight.
			↓Inflammation in WAT and liver, CLS and hepatic steatosis [90].
	Caspase-1/Caspase-11	HFD	↑Body weight and hepatic steatosis	[87]
	GsdmD	LPS injection or HFD [104] Gsdmd−/− in MCD diet [102]	↑GSDMD and fragment GSDMD-N in WAT and Liver of obese humans and mice [98, 111].	[98, 111]
			GSDMD inhibitor (Melatonin):
			↓GSDMD expression, NLRP3 activation, IL-1β in WAT [111].
			Gsdmd−/−:
			↑Lipolytic genes
			↓Hepatic steatosis and lipogenic genes [98].
	IL-1β	HFD or obese human samples	↑IL-1β in WAT and Liver of obese humans and mice [84, 109]	[84, 109]
			IL-1β−/−:
			↑WAT weight.
			= Body weight and Liver weight.
			↓Hepatic steatosis, insulin resistance and infiltration inflammatory macrophages [109].
	IL-18	ND mice or Obese human	↑ IL-18 in obese humans.	[96]
			IL-18−/− :
			Similar to Nlrp1−/− spontaneous phenotype ↑adipose tissue, glucose intolerance and insulin
			resistance, leptin levels. [96]

↑increase, promote; =equals, not modification; ↓decrease; Ø blocks; p-phosphorylated.

A-OE Adipocytes overexpression, KO knock-out, A-KO adipocytes KO, CDAA choline-deficient L-amino acid-defined, CLS crown like structures, Hep-OE hepatocytes overexpression, Hep-KO hepatocytes KO, HFD high fat diet, HSD high sucrose diet, MCD methionine-choline deficient diet, MRC mitochondrial respiratory chain, NASH Non-alcoholic steatohepatitis, si small interfering RNA, WD Western diet (FFC diet, high in fat, fructose, and cholesterol), ND normal diet.